The use of a device for providing continuous and controlled topical delivery of active agents through skin or mucosa is well known. These devices, often referred to as transdermal drug delivery systems, attempt to avoid and overcome many problems associated with other routes of drug administration—oral administration in which the drug may not be tolerated well by the digestive tract and is often required to be multiple daily dosed in order to achieve therapeutic levels (e.g., low bioavailability due to degradation or metabolism); administration by ointment, gel or cream in which the drug may be inadequately dosed or overdosed causing wide fluctuations in blood levels or therapeutic effect at the site of application, or may cause undesirable side effects of the absorbing tissues as well as interfering with the clothing and activities of the user; and administration by injection in which the delivery is typically unpleasant or painful and requiring assistance of a medical professional, leading to poor patient compliance especially in therapy for chronic diseases.
Generally speaking, transdermal drug delivery systems are commonly either reservoir-type or matrix-type devices. Both types of devices include a backing layer that forms the outer surface of the finished transdermal device and which is exposed to the environment during use, and a release liner or protective layer that forms the inner surface and which covers the adhesive means for affixing the devices to the skin or mucosa of a user. The release liner or protective layer is removed prior to application, exposing the adhesive means which is typically a pressure-sensitive adhesive. The active agent is located between the release liner and backing layer, usually solubilized or dispersed in a solvent or carrier composition.
In a reservoir-type device, the active agent is isolated from the adhesive means used to affix the device to the user. Traditionally, a reservoir system referred to a device having a pocket or “reservoir” serving to hold the active agent and was formed in or by the backing layer itself. Such a backing layer is impermeable, occlusive and typically rigid. A peripheral adhesive layer is then used to affix the device to the user. While such devices are still in use today, the term reservoir has become known as a device which employs one or more permeable layers, such as rate controlling membranes, and drug permeable adhesives layers, laminated over the reservoir (which is typically nothing more than another layer containing the drug in a carrier composition), in an effort to more effectively control the delivery rate of the active agent and attachment of the device to the user.
A matrix-type device generally comprises the active agent solubilized or dispersed in a carrier formulation which functions as both the drug carrier and the adhesive means of applying the system to the skin or mucosa. Such devices are described, for example, in U.S. Pat. Nos. 4,994,267; 5,474,783 and 5,656,286, assigned to Noven Pharmaceuticals, Inc., Miami, Fla.
Reservoir-type transdermal drug delivery systems tend to be bulkier and/or therefore less flexible and comfortable than matrix-type devices. The thicker and less flexible the device, the greater the tendency to wrinkle, fold and dislodge or loosen from the site of application. If a transdermal drug delivery system is to effectively deliver a therapeutic amount of active agent, it must remain in intimate contact with the skin or mucosa. Accordingly, reservoir-type devices work best on body areas that are flat or subject to the least amount of movement.
By reducing the overall thickness and bulk of reservoir-type systems, matrix-type devices offer improved flexibility and adherence with movement at the application site. The ability of the matrix-type device to conform to the application site and be comfortable to the user is essentially determined by the material selected as the backing layer.
The backing layer serves to retain and maintain the active agent carrier composition disposed on it in a defined size and shape, imparting strength and support to the device. The backing layer must provide protection from loss to the environment of the active agent and other components of the carrier composition, and prevent passage of substances into the transdermal system. Materials typically used as backing layers include plastic films, foils, papers and a variety of polymeric substances as described, for example, in U.S. Pat. Nos. 4,994,278 and 5,656,286.
In order to produce a transdermal drug delivery system intended to deliver an active agent locally, for example, for relief of pain or inflammation, flexibility and comfort become critical to the system's characteristics since many of the application sites are greatly contoured or subject to frequent movement. Conventional backing layers made of films are undesirable. If the backing layer is of sufficient thickness to provide the needed strength and support for the active agent carrier composition, then it typically lacks the elongation properties to provide the flexibility needed to maintain contact with the application site, as well as being uncomfortable. Conversely, if the backing layer is of sufficient thinness to provide the needed elongation properties that impart the flexibility needed to maintain contact with the application site, then it typically fails to provide the strength and support for the active agent carrier composition, as well as protection of loss from the environment.
Consequently, “soft” backings similar in appearance to the padded covering used in common stick-on bandages, such as cloth, woven and foamed materials, were utilized to achieve the needed elongation and support properties.
While variations exist in transdermal systems incorporating these soft backings, such systems intend these backing layers to serve not only as the outer protective surface, but also as the depot or storage location for receiving and retaining all or some of the active agent. In other words, the backing layer is or becomes infiltrated with the drug itself, or with a solution or mixture of the drug and a suitable solvent or polymer carrier. Typically, the active agent carrier is in a non-finite form such as a gel, ointment, liquid and the like.
Because the backing layer must therefore receive and absorb the active agent, (a) stability and potency of the drug and (b) porosity or occlusiveness of the backing layer which affects the degree of penetration of the drug and/or carrier composition into the backing layer, become important factors which often present problems with such devices.
For example, U.S. Pat. No. 5,741,510 describes a transdermal patch comprising a porous backing layer for receiving a pressure-sensitive drug containing hydrogel. The drug containing hydrogel is required to substantially penetrate into the backing layer. In order to prevent the hydrogel from becoming too viscous to properly penetrate the backing layer, the hydrogel requires chilling to keep it sufficiently fluid. The porosity of the backing layer consequently becomes important to achieve the necessary degree of penetration as well as to provide a non-occlusive patch (i.e., permit permeation of water vapor out of the system). Since the hydrogel also functions as the adhesive means for attachment of the device to the user, its application must be further controlled so as to also remain sufficiently on the surface of the backing layer.
U.S. Pat. No. 5,635,201 discloses a method and apparatus for manufacturing a wound dressing. The method includes coating an upper surface of a perforated backing material with a curable silicone mixture, blowing cold air onto the underside of the backing material, and applying heat to the silicone mixture until it is cured to a silicone gel. The cold air is applied by an air blowing unit to remove an applied silicone mixture from pores in the backing material, thereby maintaining the porosity of the wound dressing. The cold air further prevents the silicone mixture from curing before it has time to spread over the backing material.
In order to prevent the active agent and any solvents and/or polymer carrier for the active agent from passing outwardly and through the outer surface of the backing layer, some devices add a barrier layer to such outer surface. For example, U.S. Pat. No. 5,716,621 discloses the use of a moisture vapor permeable barrier layer bonded to the outer surface of a foam backing layer. The backing layer is used as the depot for the drug and its carrier composition. Since it is essential that the barrier layer be moisture vapor permeable, the patent further teaches nonadhesive techniques as the preferred method of bonding the barrier layer to the upper surface of the backing layer. Since such a transdermal system does not use a drug carrier composition which can also function to affix the system to the user, a separate adhesive means must be deposited on the inner surface of the backing layer. Such a system creates further complications.
For example, if the adhesive is incompatible with the backing layer, the attachment of the transdermal device to the user will be less than satisfactory, especially considering such devices are often desired to be worn continuously for an extended period of time and must be maintained properly in place throughout the entire period if the device is to effectively deliver a therapeutic amount. It is also important that the adhesive generally remain on the surface of the backing layer rather than fill or penetrate the cells or micropores of the backing layer, which can hinder or prevent the delivery system from delivering a therapeutically effect amount.
Stated differently, the adhesive must keep the transdermal device in intimate contact with the skin or mucosa by anchoring properly to both the backing layer and to the skin or mucosa, but without interfering with the backing layer's function of being the drug depot.
A number of techniques have been suggested for achieving such results. For example, in some devices the adhesive is applied to the backing layer in a pattern of coated and noncoated areas in order to leave some open areas of the backing layer for the drug to pass through. Alternatively, in transdermal devices made in particular shapes, the adhesive is often applied around the perimeter of the patch or in concentric circles, in yet another attempt to provide the necessary adherence to the skin, while permitting the concurrent necessary transfer of the active agent out of the backing layer. Such techniques often provide less than satisfactory results.
It is therefore an object of this invention to avoid the manufacturing and performance difficulties that are often encountered when the backing layer also functions as the substrate or storage location for the active agent and/or for the adhesive used to affix the system to the user, but still provide a flexible transdermal system which is able to conform to and remain in intimate contact with the site of topical application.
It is another object of this invention to provide a flexible transdermal system that comprises a backing layer lined with a barrier film of sufficient strength to support and anchor the other components of the transdermal system yet not interfere with the desired flexibility of the system.
It is also an object of this invention to provide a flexible transdermal system in which the barrier film lined backing layer does not “delaminate” (i.e., separate) during use of the system or upon its removal from the site of topical application.
It is a further object of this invention to provide a flexible transdermal system for delivery of active agents to a site of topical application in need of anti-inflammatory, analgesic or anesthetic therapy, such as knees, ankles and elbows, while still providing the flexibility required to remain in intimate contact with such topical application site and effect the needed therapy over the entire intended duration of use.
It is still a further object of this invention to provide a flexible transdermal system that can comfortably conform to and remain in substantially intimate contact during topical application with sites which are generally subject to frequent movement, flexing or bending, or are greatly contoured, such as knees, ankles and elbows, for at least 24 hours, and even up to 72 hours.